The Calcineurin-NFAT-Angiopoietin 2 signaling axis in lung endothelium is critical for the establishment of lung metastases
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ABSTRACT:
PROVIDER: PRJNA211919 | ENA |
REPOSITORIES: ENA
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Project description:The pre-metastatic niche is a pre-determined site of metastases, awaiting the influx of tumor cells. Here we demonstrate that the calcineurin-NFAT pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. We previously showed that DSCR-1 functions in a negative feedback loop to attenuate calcineurin signaling. Upregulation of the calcineurin pathway via loss of Dscr-1 leads to a significant increase in lung metastasis due to the increased expression of a newly identified NFAT target, Angiopoietin (Ang)-2. An increase in VEGF levels specifically in the lung versus other organ microenvironments triggers a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR-1 or the Ang-2 receptor, soluble Tie2, prevents activation of the lung endothelium inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the pre-metastatic niche and offers novel targets for lung metastases.
2015-01-01 | GSE48841 | GEO
Project description:The pre-metastatic niche is a pre-determined site of metastases, awaiting the influx of tumor cells. Here we demonstrate that the calcineurin-NFAT pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. We previously showed that DSCR-1 functions in a negative feedback loop to attenuate calcineurin signaling. Upregulation of the calcineurin pathway via loss of Dscr-1 leads to a significant increase in lung metastasis due to the increased expression of a newly identified NFAT target, Angiopoietin (Ang)-2. An increase in VEGF levels specifically in the lung versus other organ microenvironments triggers a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR-1 or the Ang-2 receptor, soluble Tie2, prevents activation of the lung endothelium inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the pre-metastatic niche and offers novel targets for lung metastases. Whole lung total RNA were harvested from wildtype or Dscr-1 null mutation mice (C57BL6/J background), and subjected to Affymetrix Mouse 430 2.0 array in duplicate conditions. Alternatively, primary cultured human lung endothelial cells (LONZA) were transfected with either siRNA, control or DSCR-1, or adenovirus expressing DSCR-1 or mock control. Adenovirally transfected lung endothelial cells were serum-starved (EBM-2 (LONZA) plus 0.5% FBS) and treated with 50ng/ml VEGF for indicated time points. After the treatments, total RNA was harvested and subjected to Affymetrix Human U133 Plus 2.0 array.
2015-01-01 | E-GEOD-48841 | biostudies-arrayexpress
Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A. bone marrow cells from C57B/6 mice were stimulated in Flt3-L suplemented media in presence or absence of calcineurin/NFAT inhibitor Cyclosporin A, samples in 3 biological replicates
2011-09-30 | E-GEOD-29094 | biostudies-arrayexpress
Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A.
2011-10-01 | GSE29094 | GEO
Project description: Not available
| S-EPMC3763962 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL) represents the most common form of lymphoma. We could show that in DLBCL cell lines the transcription factor NFAT is constitutively activated and drives the survival of a DLBCL subset. Aim of the analysis was to identify NFAT target genes in a NFAT-dependent (HBL-1) or -independent (HT) DLBCL cell line. To block NFAT activity, the DLBCL cells were treated with the calcineurin inhibitor cyclosporin A (CsA) up to 48 h. With this approach, we identified several survival-related NFAT target genes in HBL-1 cells that might explain the toxic effects of calcineurin inhibitors.
2019-11-23 | GSE140882 | GEO
Project description:Complex regulatory mechanisms control continuous maintenance of myeloid progenitors and renewal of differentiated cells. Transcription factors play a important role in these processes. Here we report that the activation the calcineurin-NFAT signaling pathway inhibit the proliferation of myeloid granulocyte-monocyte progenitor (GMP). Myeloid progenitor subtypes possessed different susceptibilities to Ca2+ flux induction and consequently differential engagement of the calcineurin-NFAT pathway. This study show that inhibition of the calcineurin-NFAT pathway enhanced proliferation of GMPs both in vivo and in vitro. The calcineurin-NFAT signaling in GMPs is initiated through Flt3-L. The inhibition of the calcineurin-NFAT pathway altered the expression of the cell cycle regulation genes CDK4, CDK6, and CDKN1A, thus enabling faster cell cycle progression. The extensive use of NFAT inhibitors in the clinic should take into account that, in addition to the immunosuppression role in lymphoid cells, these NFAT inhibitors also affect the maintenance of the myeloid compartment. Microarray technology was used to understand the effects of NFAT inhibitors on C-kit enriched lineage negative cells.
2014-12-31 | GSE47208 | GEO
Project description:Self-renewal and pluripotency are hallmarks of embryonic stem cells (ESCs). However, signaling pathways triggering their transition from self-renewal to differentiation are not well defined. Here, we report that the calcineurin-NFAT signaling pathway is both necessary and sufficient to switch ESCs from an undifferentiated state to early differentiation.To gain an insight into the function of calcinerin-NFAT signaling in ESC lineage commitment, we examined the repertoire of genes changed after LIF withdrawal alone, LIF withdrawal in the presence of cyclosporine A (CsA), a specific inhibitor of calcinerin and forced expression of active forms of calcineurin (deltaCnA) in the presence of LIF,and identified distinct classes of up and down regulated genes by calcineurin-NFAT signaling in mouse embryonic stem cells.
2011-01-01 | GSE21378 | GEO
Project description:Inhibition of calcineurin-NFAT pathway at the early stage can block somatic cell reprogramming. In order to study how the calcineurin-NFAT pathway contributes to the early stage of reprogramming, we designed this microarray experiment and tried to find out which genes or signalings were changed after inhibition of calcineurin-NFAT signaling by CSA (a specific inhibitor of calcineurin-NFAT pathway).
2015-12-01 | GSE67739 | GEO
Project description:Calcineurin-NFAT signaling is associated with a wide range of biological processes and diseases. Our previous study showed that this pathway plays a critical role in mouse embryonic stem cell (mESC) differentiation. However, its function in human ESCs (hESCs) remains unclear. Here, we report that expression of PPP3CC, the gene encoding the catalytic subunit of calcineurin, increases along with the process of hESC differentiation, and its knockdown (KD) enhances the self-renewal ability of hESCs with a simultaneous reduction in the expression of differentiation-associated markers regardless of culture conditions. Moreover, we observed that NFATC3 translocates from the cytoplasm to the nucleus when hESCs exit from a self-renewal state. These results indicate that calcineurin-NFAT signaling is activated and required during hESC differentiation. Mechanistically, we also found that in hESCs NFATC3 interacts with JUN， one of AP-1 complex subunit, and co-expression of exogenous NFATC3 and JUN upregulates lineage markers remarkably even under a self-renewal culture condition. Additionally, inhibition of this cascade represses MAPK signaling rapidly, including ERK1/2, JNK and P38. Taken together, this study delineates the importance of the calcineurin-NFATC3/JUN signaling cascade for the pluripotency maintenance of hESCs.
2020-08-04 | GSE155563 | GEO